Process for the preparation of 3-isoxazolecarboxylic acid

ABSTRACT

A process for the preparation of 3-isoxazolecarboxlic acid which is an intermediate for prepearing useful compounds is provided, said process being characterized in that a compound of formula (I) is reacted with hydroxylamine to obtain a compound of formula (II), and the compound thus obtained is treated with an alkali: ##STR1## wherein R 1  is a lower alkyl, R 2  is a carboxy protecting group, X is a halogen atom, and Y is a hydrogen atom, or X and Y together may form a single bond.

This application is a division of application Ser. No. 08/687,330, filedAug. 7, 1996 now U.S. Pat. No. 5,696,271 which is the national stage ofPCT/JP95/00211 filed Feb. 15, 1995.

FIELD OF THE INVENTION

This invention relates to a process for the preparation of3-isoxazolecarboxylic acid which is useful as an intermediate forproducing condensed imidazopyridine derivatives which are described, forexample, in Japanese Patent Publication (Kokai) No. 286973/1993 and itscorresponding European Patent Publication No. 556008A.

DESCRIPTION OF PRIOR ART AND PROBLEMS TO BE SOLVED

3-Isoxazolecarboxylic acid has been synthesized by various methods. Forinstance, as shown in the reaction scheme below, ethoxycarbonylnitrileoxide was reacted with vinylethyl ether to obtain ethyl5-ethoxyisoxazoline-3-carboxylate, and then the ethoxy group was removedto produce ethyl 3-isoxazolecarboxylate Raymond Paul and SergeTchelitcheff, Bull. Soc. Chim. France 1962, 2215!. ##STR2##

This method, however, has a disadvantage that the ethylchloroximinoactate, a starting material of the nitrile oxide, upontouching skin, could cause a rash on the skin.

Further, in J. Chem. Soc., Chem. Commun., 17 (1991), a method for thepreparation of ethyl 3-isoxazolecarboxylate is described. This methoduses ethyl chloroximinoacetate as a starting material, which also causesa rash on the skin, and it is hard to handle.

J. Org. Chem. 26, 2976 (1961) discloses, a method for the preparation of3-isoxazolecarboxylic acid as shown in the reaction scheme below. Thismethod is not suitable for industrial production of the acid because ofits poor reaction efficiency. ##STR3##

In view of the above problems, the inventors of the present inventionhave explored an industrially-applicable synthetic method for3-isoxazolecarboxylic acid, and they have developed a novel process forthe preparation of the acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of3-isoxazolecarboxylic acid of the formula (III): ##STR4## characterizedin that a compound of the formula (I): ##STR5## wherein R¹ is a loweralkyl, R² is a carboxy protecting group, X is a halogen atom, and Y is ahydrogen atom, or X and Y together may form a single bond, is reactedwith hydroxylamine to obtain a compound of the formula (II): ##STR6##wherein R¹ and R² are as defined above, and then the resultant productis treated with alkali.

Each step of the above overall process also constitues anotherinvention. That is, the process for the production of5-alkoxyisoxazoline-3-carboxylic acid derivatives of the above formula(II), which process is characterized in that a compound of the formula(I): ##STR7## wherein R¹, R², X and Y are as defined above, is reactedwith hydroxylamine, is also part of the present invention.

Further, a process for the production of 3-isoxazolecarboxylic acid ofthe formula (III): ##STR8## which process is characterized in that acompound of the formula (II): ##STR9## wherein R¹ is a lower alkyl andR² is a carboxy protecting group, is treated with alkali, is also partof the present invention.

The process of the present invention may be shown in the followingreaction scheme. ##STR10##

In step 1!, the compound (a) or (b) of the formula (I) is reacted withhydroxylamine. The reaction temperature is usually from about -20° toabout 80° C., preferably from 0° to 40° C. The reaction is carried outin the presence or absence of a solvent. As the solvent, ethers (ethylether, tetrahydrofuran, etc.), aromatic hydrocarbons (benzene, toluene,etc.), and halogenated hydrocarbons (chloroform, dichloromethane, etc.)may be exemplified. Hydroxylamine may be used preferably in an amount ofabout 1 to 4 molar equivalents to the starting material.

The starting materials (a) and (b) may be prepared according to thefollowing reaction scheme as described in L. F Tietze, Synthesis, 274(1988): ##STR11##

Although this reaction produces a mixture of the compounds (a) and (b),the compound (a) is readily converted into the compound (b) duringisolation and purification for example, by distillation, thereby thesingle compound (b) is obtained. The compound (a) is known to beunstable as intermediate, and it is believed that the compound (a) mightbe converted into the compound (b) by heating (higher than about 60° C.)or under basic conditions. Incidentally, in the following Example 1, itbas been confirmed by NMR analysis that the mixture in which thecompound (a) was a main product was produced at the first step.

Therefore, irrespective of the contents of the starting materials (a)and (b) in the mixture, the result would be the same as the case whenthe compound (a) or (b) is solely used in the reaction. Accordingly,these starting materials (a) and (b) can be used for the reactionwithout isolation and purification.

The above step 2! is the process in which elimanation of R¹ OH andhydrolysis of ester are carried out in a single step.

The reaction is usually carried out in a solvent such as water andalcohols, and preferably at a temperature from about 0° to 50° C. Alkalimay be used preferably in an amount of about 1 to 10 molar equivalentsto the compound (II).

In general, elimination of an alkoxy group (dealcohol) is usuallycarried out under acidic condition or heating. It is therefore expectedthat the elimination of the alkoxy group may be achieved under one ofsuch conditions alone. In the present invention, however, hydrolysis ofthe ester must be conducted coincidently, and hence the alkali treatmentis added.

Theoretically, a carboxy protecting group R² can be optionally selectedfrom conventional protecting groups as far as it is not deprotectedduring the reaction (1) but deprotected during the reaction (2). Takingthe yield and after-treatment into consideration, however, lower alkyls(in particular, methyl, ethyl, propyl, etc.) or aralkyls (in particular,benzyl, naphthylmethyl, etc,), and the like are preferable.

Examples of the alkali used in the step 2! are hydroxide of alkalimetals, alkaline earth metals or ammonium group, and the preferredalkalis are NaOH, KOH, and the like.

The lower alkyls for R¹ are straight or branched C₁ -C₆ alkyls such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, i-pentyl, n-hexyl, and i-hexyl. C₁ -C₃ alkyl is preferred.

The halogens for X are Cl, Br, and the like, and Cl is preferred.

The following examples are provided to illustrate the present inventionin more detail, but they are not intended to limit the scope of thepresent invention.

EXAMPLE 1 ##STR12##

Vinylethyl ether(480 ml) is added to 280 ml of oxalyl chloride at roomtemperature, and the mixture is stirred for 4 hours to obtain a reactionmixture which contains ethyl 4-ethoxy-4-chloro-2-oxobutylate as a mainproduct.

Ethyl 4-ethoxy-4-chloro-2-oxobutyrate (compound (a)) ##STR13##

NMR (CDCl₃):δ1.24 (3H,t), 1.38 (3H,t), 3.49(1H,m), 3.58(1H,q),3.65(1H,m), 3.94(1H,q), 4.34(2H,q), 6.01(1H,m) ppm.

The reaction mixture is cooled with ice, and 1680 ml of dry ethanol areadded slowly while avoiding occurrence of exothermic reaction, and then173 g of hydroxylamine hydrochloride is added, and the mixture isstirred at room temperature for 4 hours. The reaction mixture is pouredinto 3400 ml of water and extracted with ethyl acetate. The extract iswashed sequentially with water, an aqueous solution of sodiumbicarbonate, and a saturated brine, and dried over anhydrous sodiumsulfate. The solvent is distilled off to obtain 468 g of oily residuewhich contains ethyl 5-ethoxyisoxazoline-3-carboxylate as a mainproduct. To this residue is added 750 ml of 5N sodium hydroxide, and themixture is stirred at room temperature for 2 hours. To the reactionmixture, 152 ml of concentrated hydrochloric acid is added, and 950 mlof methyl ethyl ketone is added thereto. An additional amount ofconcentrated hydrochloric acid is added to render the mixture acidic topH 2. The organic layer is separated, treated with active carbon andanhydrous magnesium sulfate, and evaporated. The resulting residue iscrystallized from ethyl acetate, filtered, and recrystallized from ethylacetate to obtain 97 g of 3-isoxazolecarboxylic acid.

Melting point: 149°-150.5° C. (It is described as 149° C. in R. Cramerand W. R. McCleallan, J. Org. Chem., 26, 2976 (1961))

NMR(d₆ -DMSO): δ6.93(1H,d,J=1.8Hz), 9.14(1H,d,J=1.8Hz), 14.0(1H,br) ppm.

Elementary analysis for C₄ H₃ NO₃ :

Calculated (%): C, 42.49; H, 2.67; N, 12.39

Found (%): C, 42.25; H, 2.80; N, 12.12

EXAMPLE 2 ##STR14## (1) Ethyl 5-ethoxyisoxazoline-3-carboxylate

17.22 g of 4-ethoxy-2-oxo-3-butenoic acid prepared according to themethod of L. Tietze et al. (Lutz-F. Tietze, Heinrich Meier and EdgarVoss, Synthesis 1988, 274) are dissolved in 50 ml of anhydrous ethanol,and 7.34 g of hydroxylamine hydrochloride is added thereto, and themixture is stirred at room temperature for 4 hours. The reaction mixtureis added with water and extracted with methylene chloride. The organiclayer is washed with water, dried, and evaporated. The resulting residueis distilled under reduced pressure to yield 14.3 g of ethyl5-ethoxyisoxazoline-3carboxylate. (yield 76%)

Boiling point: 113°-115° C. (2 mmHg)

NMR (CDCl₃):δ1.22 (3H,t), 1.38 (3H,t), 3.0-3.4 (2H,m), 3.5-4.0 (2H,m),4.36 (2H,q), 5.71 (1H,m) ppm.

Elementary analysis for C₈ H₁₃ NO₄ :

Calculated (%): C, 51.33; H, 7.00; N, 7.48

Found (%): C, 51.08; H, 7.10; N, 7.25

(2) Isoxazole-3-carboxylic acid

200 ml of 1N sodium hydroxide are added to 24.75 g of ethyl5-ethoxyisoxazoline-3-carboxylate prepared according to the method ofprocess (1), and the mixture is stirred at room temperature for 2 hours.The reaction mixture is acidified with 26 ml of concentratedhydrochloric acid, and condensed to about 1/3volume under reducedpressure, and cooled. The separated crystalline compound is filtered,washed twice with 30 ml of cold water and dried to yield 13.43 g of thetitled compound.

Melting point: 149°-152° C.

What is claimed is:
 1. A process for the preparation of3-isoxazolecarboxylic acid of the formula (III): ##STR15## characterizedin that a compound of the formula (II): ##STR16## wherein R¹ is a loweralkyl and R² is a carboxy protecting group, is treated with an alkali.